Schizophrenia is a complex psychiatric disorder that is extremely difficult to model in rodents because of structural difference between human and mouse brains, lack of clear pathological hallmarks of the disorder, and inability of mice to demonstrate human psychiatric phenotypes such as delusion, hallucination, or depression. This argues for models to create a piecemeal of different components in schizophrenia with discrete endpoints in behavioral, physiological, and molecular analyses. Such an approach has proved useful in generating and analyzing schizophrenic rodent models. Both neuregulin-1 (NRG1) and its receptor ErbB4 are susceptibility genes of schizophrenia. Recent evidence suggests a gain-of-function of NRG1 signaling in the prefrontal cortex (PFC) in schizophrenic patients. Increased expression of type I NRG1 and CYT-1/JMa ErbB4 have been reported in the PFC of patients with schizophrenia. Moreover, NRG1 signaling was found to be enhanced in the same area of postmortem brains from schizophrenic patients. Despite of the clinic evidence for NRG1/ErbB4 gain-of-function in schizophrenia, there has not been such a rodent model. This appears to be a bottle neck for further in vivo studies of cellular, molecular as well as behavioral deficits and pathological mechanisms of NRG1 and ErbB4 mutations. In preliminary studies, we demonstrated that NRG1, via ErbB4, regulates activity-dependent GABA release in the PFC. Therefore, we propose to generate and characterize GAD67-ErbB4 transgenic mice overexpressing human CYT-1/JMa ErbB4. The R21 Phase has three Specific Aims: 1) Generation of GAD67-ErbB4 transgenic mice;2) Determine whether NRG1 signaling and induced activity-dependent GABA release are increased in GAD67-ErbB4 transgenic mice;and 3) Determine whether NRG1 regulation of GABA transmission is increased in GAD67-ErbB4 transgenic mice. The R33 Phase has two Specific Aims: 1) Determine whether NRG1 suppression of pyramidal neuron activity is up-regulated in GAD67-ErbB4 mice and 2) Determine whether GAD67-ErbB4 transgenic mice can model working memory deficits, positive and negative symptoms and attentional deficits in schizophrenia. It is our hope that the gain-of- function model of ErbB4 signaling will provide critical insight into pathogenic mechanisms and pathways of NRG1 and ErbB4, two important susceptibility genes. The transgenic mice might be useful for testing chemicals and biological reagents that could facilitate the development of novel therapeutic interventions of schizophrenia. Moreover, successful generation and characterization of GAD67-ErbB4 transgenic mice will offer a proof of principle for other NRG1 gain-of-function models in different regions of the brain. This is a proposal to generate GAD67-ErbB4 transgenic mice over-expressing human CYT-1/JMa ErbB4 to model neurotransmission and behavioral deficits in schizophrenia. The gain-of-function model of ErbB4 signaling will provide critical insight into pathogenic mechanisms and pathways of NRG1 and ErbB4, two important susceptibility genes of schizophrenia.